Human growth factor-enhanced regeneration of transplantable human hematopoietic stem cells in nonobese diabetic/severe combined immunodeficient mice

Self-renewal is considered to be the essential defining property of a stem cell. Retroviral marking, in vitro amplification, and serial transplantatio n of human cells that can sustain long-term lymphomyelopoiesis in vivo have provided evidence that human hematopoietic stem cell self-renewal occurs b oth in vitro and in vivo. To investigate whether this process can be manipu lated by cytokines, we administered two different combinations of human gro wth factors to sublethally irradiated nonobese diabetic/severe combined imm unodeficient (SCID) mice transplanted with 10(7) light-density human cord b lood cells and then performed secondary transplants to compare the number o f transplantable human lymphomyeloid reconstituting cells present 4 to 6 we eks post-transplant. A 2-week course of Steel factor + interleukin (IL)-3 granulocyte-macrophage colony-stimulating factor + erythropoietin (3 times per week just before sacrifice) specifically and significantly enhanced th e numbers of transplantable human lymphomyeloid stem cells detectable in th e primary mice (by a factor of 10). Steel factor + Flt3-ligand + IL-6 (usin g either the same schedule or administered daily until sacrifice 4 weeks po st-transplant) gave a threefold enhancement of this population. These effec ts were obtained at a time when the regenerating human progenitor populatio ns in such primary mice are known to be maximally cycling even in the absen ce of growth factor administration suggesting that the underlying mechanism may reflect an ability of these growth factors to alter the probability of differentiation of stem cells stimulated to proliferate in vivo. (C) 1999 by The American Society of Hematology.